NF-κB Is a Negative Regulator of IL-1β Secretion as Revealed by Genetic and Pharmacological Inhibition of IKKβ

Florian R. Greten, Melek C. Arkan, Julia Bollrath, Li Chung Hsu, Jason Goode, Cornelius Miething, Serkan I. Göktuna, Michael Neuenhahn, Joshua Fierer, Stephan Paxian, Nico Van Rooijen, Yajun Xu, Timothy O'Cain, Bruce B. Jaffee, Dirk H. Busch, Justus Duyster, Roland M. Schmid, Lars Eckmann, Michael Karin

Research output: Contribution to journalArticlepeer-review

536 Scopus citations

Abstract

IKKβ-dependent NF-κB activation plays a key role in innate immunity and inflammation, and inhibition of IKKβ has been considered as a likely anti-inflammatory therapy. Surprisingly, however, mice with a targeted IKKβ deletion in myeloid cells are more susceptible to endotoxin-induced shock than control mice. Increased endotoxin susceptibility is associated with elevated plasma IL-1β as a result of increased pro-IL-1β processing, which was also seen upon bacterial infection. In macrophages enhanced pro-IL-1β processing depends on caspase-1, whose activation is inhibited by NF-κB-dependent gene products. In neutrophils, however, IL-1β secretion is caspase-1 independent and depends on serine proteases, whose activity is also inhibited by NF-κB gene products. Prolonged pharmacologic inhibition of IKKβ also augments IL-1β secretion upon endotoxin challenge. These results unravel an unanticipated role for IKKβ-dependent NF-κB signaling in the negative control of IL-1β production and highlight potential complications of long-term IKKβ inhibition.

Original languageEnglish
Pages (from-to)918-931
Number of pages14
JournalCell
Volume130
Issue number5
DOIs
StatePublished - 7 Sep 2007
Externally publishedYes

Keywords

  • MOLIMMUNO
  • SIGNALING

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